One of most unexpected and surprising recent areas of scientific investigation are interactions of the intestinal microbiome on health and disease. Interesting findings include the impact of the microbiome on heart disease due to metabolites generated by bacterial flora promoted by meat consumption, and the impact of the microbiome on obesity. The interactions between the microbiome and the host are likely bidirectional, with the host state impacting the diversity and range of the intestinal microbiome, as well as the intestinal microbiome impacting host health and disease state. Understanding these interactions and how they influence and are influenced by disease is an exploding area of biology with profound implications for health. However, a huge challenge in this work is the difficulty and expense in performing the experiments, in either humans or mammalian models like mice. Diseases, especially chronic neurodegenerative diseases, are especially difficult to investigate for these interactions because of the advanced age of the individuals and their physical condition. We propose to use Drosophila for pioneering studies to assess if the microbiome is impacted by degenerative disease in the animal, and if the microbiome impacts the presentation of disease. Our laboratory has a special focus on amyotrophic lateral sclerosis/frontotemporal dementia and Parkinson's disease, and we propose to initiate studies with robust models for these disorders. In Aim 1, we will assess the impact of neurodegenerative disease on the microbiota of the animal. We will define the gut microbiome of animals over progression of disease longitudinally in the adult, using a range of critical models for these diseases. These studies will define if the microbiome is altered upon disease onset or progression, as well as provide a comparison of this impact between different models of disease. In Aim 2, we will investigate the reciprocal interaction, to determine if the gut microbiome impacts progression and severity of neurodegenerative disease. We will grow disease models germ free on axenic medium and assess key benchmarks and features of the disease phenotype. These experiments will define whether the gut microbiota of the animal itself has an impact on the onset, progression or severity of disease. Here we take advantage of the fact that experiments with gnotobiotic flies are straightforward, while experiments with gnotobiotic vertebrates are quite difficult and expensive. The findings of these Aims will define the reciprocal impact between the microbiome and the neurodegenerative disease state of the animal, to assess these inter-related connections. These studies will establish a simple model foundation for microbiota-animal interactions in neurodegenerative disease, providing predictions for more complex-but slower and far more expensive-animals.